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Venkatraman Ramakrishnan - Biographical

From Chidambaram to Cambridge: A Life in Science

Childhood
I was born in 1952 in Chidambaram, an ancient temple town in Tamil Nadu
best known for its temple of Nataraja, the lord of dance. When I was born, my
father, C.V. Ramakrishnan, was away on a postdoctoral fellowship in Madison,
Wisconsin, with the famous enzymologist David Green. Because he came
from a poor family, he did not think that he could support my mother and
me on his postdoctoral income, so he went alone. I often joke that but for
this, I would have been born in Madison and could have gone on to become
President of the United States. In fact, I first saw him when I was about six
months old. My mother, R. Rajalakshmi, taught at Annamalai University in
Chidambaram, and during the day, I was well cared for by aunts and grandparents
in the usual way of an extended Indian family. When I was about a
year and a half, my father left again, this time with my mother, to go to Ottawa
on a National Research Council fellowship. They returned a little over a year
later, and during their absence I was brought up by my grandmother and my
aunt Gomathi, to whom I remain close to this day.

When I was three, my parents moved to Baroda (now appropriately called
by its Gujarati name of Vadodara, which refers to the abundance of banyan
trees that the city used to have), where my father was appointed at an
unusually young age to head a new department of biochemistry at the
Maharaja Sayajirao (M.S.) University of Baroda. When he started the department,
there was just some empty lab space with no equipment or people. He
managed to acquire a low-speed table-top centrifuge, and would get blocks
of ice from a nearby ice factory, crush them, and place them around the
centrifuge so that his samples would remain cold during enzyme purification.
With this setup he managed to publish two papers in Nature in quick
succession. Within a few years, the department was well established in both
teaching and research, and equipped with instruments, a cold room and an
animal house.

Unusually for an Indian man of his generation, my father, being aware of
my mother's intellectual abilities, encouraged her to go abroad by herself to
obtain a Ph.D. She obtained a fellowship in McGill University to do a Ph.D.
in psychology, where one of her mentors was the famous psychologist Donald
Hebb, whose theories presaged modern ideas about synaptic plasticity as a
basis for memory and behavior. Probably because she felt guilty about leaving
my father and me behind, she finished her Ph.D. in under 18 months, which must be something of a record. When she returned, she could not find a suitable
position in the Psychology Department in Baroda. Instead she used her
analytical skills to help my father in his research, working initially as a CSIR
pool officer, which was a temporary scheme by the Government of India to
support scientists returning from abroad. This was the beginning of a lifelong
collaboration in their work. My childhood and adolescence were filled
with visiting scientists from both India and abroad, many of whom would stay
with us. A life of science struck me as being both interesting and particularly
international in its character.

My move to Baroda was something of a culture shock initially because until
the age of three I only spoke Tamil, a language that I unfortunately no longer
speak well. One of my earliest memories is of standing in a playground
not being able to understand a word of the Gujarati the children were speaking.
This feeling of being an outsider has remained with me for much of my
life as my career has taken me to various countries. Because my parents did
not speak Gujarati either, they enrolled me in what was then the only English
language school in town, the Convent of Jesus and Mary School, which was
located next to a large military base. After kindergarten, my mother persuaded
the school to let me skip a grade. Shortly after my sister Lalita was born
in 1959, my family went to Adelaide, Australia in 1960–61 where I studied in
fourth and part of fifth grades. I remember the year in Adelaide as one of
the most carefree years of my childhood, and returned with an Australian
accent that my former schoolmates could hardly understand. Because of
the six month difference between the Australian and Indian school years,
I effectively again skipped a grade on my return. The rest of my schooling
was at the Convent School. By that time, there were other English schools
in Baroda, and the nuns who ran the school decided to convert it to a girls'
school and no longer admit boys. They allowed those boys who had enrolled
to stay on, but by attrition, our class kept losing boys, so there was a roughly
four to one ratio of girls to boys when I graduated. Perhaps because of this
and the fact that my mother and sister both went into science, I have felt
perfectly comfortable among women even when I am the only male
present, and there have been times when my lab has consisted almost entirely
of women.

During the 7th – 9th grades, I dropped from being at or near the top of
my class to being in the bottom third. Rather than studying, I spent my time
playing and reading novels and other extracurricular books. Luckily, in my
last two years I had a dedicated science and mathematics teacher, T.C. Patel,
who made those subjects come alive. A strict disciplinarian, he nevertheless
had a twinkle in his eye as he would expose us to clever ideas and difficult
problems. This sparked my interest in my studies again, and I graduated
second in my class overall despite the fact that I did very poorly in Hindi, a
language that I never managed to learn well.

Choosing Basic Science
By the time they finished high school, students in India were separated,
as they are in England but not in America, into those who are going into
science, medicine or engineering, and those who plan to study the arts or
humanities. Although I liked literature and did well in my English class,
studying English was never really an option I considered seriously, especially
given the scientific environment in which I grew up. Additionally, the
cultural climate in India makes it difficult for good students to choose to
study the humanities unless they are particularly strong willed, because
parents are too often opposed to what they see as a risky career choice.
Accordingly, I enrolled in the pre-science course at my local university, the
M.S. University of Baroda. This was a one-year preparatory course before
students chose to go into medicine, engineering or basic science. The
pre-science course had an excellent curriculum in both physics and mathematics,
largely due to forward thinking faculty in those departments.
However, the teaching of botany and zoology was very old-fashioned and
involved memorization of lots of facts in a relatively unconnected and
tedious way. As a result, I was not particularly interested in the life sciences
at that stage.

A critical decision that students have to make after their pre-science year
is whether to go into medicine or engineering. Generally, those students
who did not get accepted into either of these went into basic sciences as
a last resort. My mother, however, had just become aware of the National
Science Talent Search Scholarship by the Government of India, which was
modeled after the Westinghouse (now Intel) Science Talent scholarships in
the U.S.A. A condition was that the recipient had to major in a basic science.
She encouraged me to take the scholarship exam, and arranged for me to do
the required research project with a colleague of hers in the Biochemistry
Department on quantifying nitrogen fixation by leguminous plants, which
was somewhat ironic given my general apathy towards biology courses.

At the end of the year, I also took national entrance exams for the famous
Indian Institutes of Technology (IITs) and for the Christian Medical College
in Vellore, one of the finest medical schools in India, but which had a very
small quota for males since it was founded to train female doctors. I did not
do well enough to qualify for admission to either institution. However, as a
result of doing well in my university exams, I was offered admission to study
medicine in Baroda. In the meantime, however, I was offered the National
Science Talent Scholarship. I had made an agreement with my father, who
wanted me to study medicine, that if I was awarded this scholarship I could
choose to study basic science. That decided, there was the further question of
where to do my undergraduate studies. I briefly considered going to Madras,
which would have reconnected me with my Tamil roots, but a faculty member
in the physics department in Baroda, S.K. Shah, told me about a brand new
curriculum they were introducing for their undergraduate course. It began
with the Berkeley Physics Course, and was supplemented by the Feynman Lectures on Physics before moving on to more specialized areas. I therefore
decided to enroll in the B.Sc. course in physics in Baroda, my hometown.
Since I was only 16 when I began this course, I sensed that my parents,
especially my father, were relieved that I was not leaving home at an age when
they felt I was not sufficiently mature emotionally.

My teachers in physics, especially S.K. Shah and H.S. Desai, were very
excited to be teaching the new curriculum for the first time, and their
enthusiasm was infectious. I also had several excellent mathematics teachers,
including the scholarly S.D. Manerikar, who discarded our exam-oriented
Indian textbooks and taught us from books like Hardy's "A course of pure
mathematics" and Courant's textbooks of calculus. It was during this time that I first met Sudhir Trivedi, who has gone on to a successful career in
applied physics in the U.S.A. and become a lifelong family friend. When we
had a boring class, we would often skip it. Once he and I sat near an open
window and decided to jump out of it as soon as attendance was taken to go
off and have tea and snacks at a nearby restaurant. His jump created a loud
thud so I could not follow because the professor was staring directly at me.

Towards the end of my undergraduate studies I had to decide where to
go to graduate school. The normal route for science students was to do a
master's at some university in India before thinking of going abroad. As
a Science Talent Scholar who was doing well, I would have been accepted
almost anywhere. However, my parents were doing a short sabbatical at the
University of Illinois in Urbana at this time, so it was tempting to spend the
summer with them and go on to graduate school in the United States. By the
time I applied, it was too late to take the GRE and without it almost no universities
would consider my application. The University of Illinois accepted
me into their graduate program in physics initially, but when they found out
I was not yet 19 years old and had taken almost no non-science courses, they
changed their minds and said I would have to enroll as an undergraduate!
Needless to say, this was not an option I was prepared to consider, not least
because it would have been impossible financially. At about this time, my
chairman N.S. Pandya brought to my attention a letter from the physics
department at Ohio University, which said they were looking for qualified
students for their graduate program. I wrote them a letter of inquiry and
soon afterwards was accepted with a fellowship. I was living alone when
the acceptance arrived, and was absolutely thrilled to be going to graduate
school in the U.S.A., a land I associated with many of the great scientists
whose textbooks I had studied, including Feynman, Purcell and others. I
arrived in America a month after my 19th birthday, and spent the summer in
Champaign-Urbana with my parents. I sat in on a number of mathematics
and physics courses there, which helped ensure that I did not have serious
deficiencies in my readiness for graduate school.

Graduate School in the U.S.A.
When I got to graduate school in Ohio, I was surprised to see that over half
of our class consisted of foreigners, many of them from India. I passed the
obligatory comprehensive exam after two years of coursework, and then
chose to work in solid-state theory with Tomoyasu Tanaka. For my proposal,
I had considered doing some theoretical work on biological systems, but
since neither he nor I knew any biology, this did not go anywhere. The
problem I took on was to look at ferroelectric phase transitions in potassium
dihydrogen phosphate. This was a particularly difficult time for me, since
I had no feel for the problem or even what the basic questions were. It
was the first time in many years that I felt I had chosen the wrong field. At
the same time, I found myself tremendously interested by the articles in
biology in Scientific American, to which I have subscribed off and on through the years. It appeared that hardly a month went by without a major breakthrough
in the life sciences, whereas physics was having a hard time making
any fundamental progress. Certainly I felt that if I continued in physics, I
would be doing boring and tedious calculations rather than making really
interesting advances. The result was that I felt so frustrated that I withdrew
from my thesis work and spent an inordinate amount of time on extracurricular
activities. I went hiking and hopped on freight trains with my
good friend and class mate Sudhir Kaicker, learned about western classical
music from another friend, Anthony Grimaldi, played on the chess team,
read literature, and went to concerts. In short, I did everything except make
progress on my work. Tomoyasu was far too kind and patient, but even he
would get worried every few months and ask how I was getting on. I was too
embarrassed to tell him that I wasn't getting on at all! I often joke that if
I had graduate students like me, I'd fire them! In hindsight, I feel that
given my aptitude and tendencies, I made a mistake in choosing theory over
experiment for my thesis work, and I might have done better under someone
like Ron Cappelletti (now at NIST), who was not only a fine experimentalist
but also tougher and less likely to tolerate an irresponsible student.
Interestingly, I later became good friends with Ron.

It was during this time that I met Vera Rosenberry, who was majoring in
painting and was introduced to me by mutual friends because, unusually
for the early 1970s in Ohio, we were both vegetarian. After an intermittent
courtship that lasted only 11 months in total, we were married in 1975. She
has been my companion and friend ever since, and has not only done most
of the work of raising our children but uprooted herself many times to move
with me all over the U.S.A. and to England. The emotional support and
stable home environment she provided has been invaluable to me and my
work. During that time, in addition to painting, she also became a children's
book writer and illustrator, and has published over 30 books.

After my marriage at the age of 23, I was suddenly no longer alone but had
a wife and a five-year-old stepdaughter, Tanya Kapka. This sudden change
in my responsibilities made me realize that I had to get on with my career. I
produced a passable thesis in the next year and obtained a Ph.D. in physics
in 1976 just a month before our son Raman was born. But by that time I had
already decided I was going to switch to biology.

Transition to Biology
Since I hardly knew any biology, I felt I needed formal training of some sort.
I could go to graduate school again, with the option of getting a second
Ph.D. or go to medical school, which was ironic since I had turned down
the opportunity to do precisely that when I was younger. I took the MCAT
(a nationwide medical college entrance exam) but despite scoring in the
99th percentile in all the subjects, I only got one interview (at Yale) because
I was not a U.S. citizen or even a permanent resident at that point. During
that interview, I said I was mainly interested in research and not interested in practicing medicine since I felt the U.S. medical system involved a fundamental
conflict of interest between doctor and patient. Needless to say, I was
not selected. However, I had also written to a number of graduate programs.
Many of them said that they would not accept someone who already had a
Ph.D. The chairman of the Molecular Biophysics and Biochemistry (MB&B)
department at Yale, Franklin Hutchinson, wrote to me saying that while they
could not take me as a graduate student, he would circulate my CV to faculty
members for a potential postdoctoral position. Two of them responded: One
was Don Engelman, and the other, ironically, was Tom Steitz, with whom
I shared the Nobel Prize. Although I found their work very interesting, I
thought doing a postdoc directly from a degree in physics would leave me
with too narrow a background in biology to be an effective scientist. So when
three schools accepted me into their graduate program, I chose to go to the
University of California, San Diego (UCSD), partly because of its large and
diverse faculty and partly because La Jolla seemed an easy place in which to
bring up young children.

During the first year, I did several lab rotations in biology and took as many
undergraduate courses as I could possibly manage, including genetics, taught
by Dan Lindsley, a well-known Drosophila geneticist, and biochemistry, where
I was inspired by the brilliant and enthusiastic lectures of Paul Price. During
a rotation project in Milton Saier's lab, which was studying sugar transporters
in bacteria, I was asked to measure the rate of sugar uptake in various
mutants. The idea was to pipette 20 μl of a stock of 14C glucose into the tubes
containing cultures at time zero, and then withdraw aliquots at regular intervals
and measure the amount of glucose uptake by filter binding. I asked
how they measured such a small volume as 20 μl. The technician showed me
a micropipettor and how to set the volume and use it. We started, but as soon
as I had plunged the micropipettor into the radioactive glucose solution, she
screamed at me, "What do you think you're doing? You have to use TIPS!"
This episode has always made me more tolerant when my students do something
out of ignorance resulting from lack of complete communication.

My first year in UCSD was tremendously exciting. For the first time in my
life, I was at a university that was at the forefront of international research. I
also made some wonderful friends, including Robert Anholt, now a professor
in North Carolina who works on olfaction, and Mark Troll, a brilliant physical
chemist who many years later married my sister.

In my second year, I settled down to do research in Mauricio Montal's
lab. Mauricio had developed an ingenious method of incorporating
conducting channels into lipid bilayers formed by bringing together two
defined monolayers, and was thus doing single molecule biophysics at a time
when nobody called it that. Around this time, however, I read an article in
Scientific American by Don Engelman and Peter Moore about their ribosome
work, and became interested in it. It also struck me that there was no longer
any reason to continue on to obtain a second Ph.D. because I felt I had
acquired the background I needed. I therefore wrote to Don Engelman,
one of the two people from Yale who had responded to me earlier. Don was interested in membrane proteins, a subject I was already working on in
Mauricio's lab. Don wrote back and said that he and Peter had a position
open on their ribosome project, and I could always work on membrane-related
projects once I got there. Peter arranged to meet me in San Diego in early
1978 and offered me a postdoctoral position soon afterwards. Thus began my
lifelong interest in ribosomes.

Postdoctoral Work in Peter Moore's Lab at Yale
Peter Moore ran a very small lab with generally no more than 4 or 5 people.
Among them was Betty Rennie (now Freeborn), who taught all of the lab
members how to purify ribosomes, reconstitute them and assay them. The
specialized methods I learned in Peter's lab were invaluable to me twenty
years later when I started tackling the structure of the 30S subunit that led
to the Nobel Prize. Peter has been a lifelong role model. He is brilliant,
rigorous, fair, straightforward and honest with his opinions, and has been
a supportive mentor all my life. In his lab I participated in the long term
project of mapping the spatial location of the proteins in the 30S subunit,
which involved reconstituting ribosomes in which a specific pair of proteins
were replaced by their deuterated counterparts. This was followed by smallangle
neutron scattering experiments at Brookhaven National Laboratory,
which would yield the distance between the centers of mass of the two
deuterated proteins. I managed to map about a third of the proteins during my stay there, as well as contribute to the use of Bayesian methods to obtain
the best possible estimates from the data.

Postdoctoral work combined with a family with two young children did
not leave me much time to socialize with fellow students or postdocs. But
we did have a number of good friends because we lived in Yale housing. I
also remember these years as being particularly happy, since I was finally
making progress on a real research project and felt that my career was finally
beginning to take shape. This feeling quickly ran into reality when I applied
for a large number of faculty positions during my final year at Yale, and
did not get a single interview. This was partly because of my rather unusual
career path, the fact that my degrees were from less than first-rate
institutions, and perhaps more importantly, universities did not know what to
think of a physicist turned biologist using an esoteric technique like neutron
scattering. I was beginning to get very discouraged when two openings finally
materialized. One of these was a limited-term position at the National Bureau
of Standards with Alex Wlodawer. The other was the result of a phone call
by Don Engelman to Wally Koehler at Oak Ridge National Laboratory, who
was looking for a biologist to hire for their new small-angle neutron facility. I
chose the Oak Ridge position because it seemed more stable and permanent,
and I was told that I could have a joint appointment in the Biology Division
and be able to carry out my own research in addition to collaborative
experiments using neutron scattering. I should have waited until the end of
the school year to move, but instead chose to do so in February during an
ice storm.

An Interlude in Oak Ridge
Soon after I arrived in Oak Ridge, I realized that I had completely misunderstood
my position. The Biology Division saw me entirely as an employee of the
neutron scattering facility, and would not commit any resources to support
me, although they gave me some space in an empty lab. I tried to remain
positive and told my boss Wally Koehler that I could apply for NIH grants
to fund my own research. He replied that it would look bad if I got external
funding while senior scientists in the Biology Division were struggling, and
moreover he had not hired me to be a biologist but to attract biologists to the
use of neutrons. I found this attitude insulting and ignorant of both the way
biology is done and the rather peripheral role that neutrons play in tackling
important biological problems. As a result, I began looking for alternatives
within a month after arriving in Oak Ridge, despite the fact that we had foolishly
just bought a house.

While I was looking for a job, I talked to various people in the Biology
Division and identified several projects where neutron scattering could
provide some useful information. In the Division, I shared an office with
Rose Feldman, a longstanding technician who worked for Salil Niyogi. Rose
was my psychological support in what would otherwise have been a very difficult
year. Moreover, I began collaborations with Mark Donnelly and Rick Wobbe, who both became lifelong family friends along with Mark's wife Veta
Bonnewell. I have never made so many longstanding friends in such a short
time. One of the most useful collaborations was work on the nucleosome
with Gerry Bunick, Ed Uberbacher and Don and Ada Olins. This sparked an
interest in chromatin that continued until 1998, when I gave it up to concentrate
entirely on the ribosome.

Starting an Independent Career at Brookhaven
The Yale neutron effort on ribosomes was the direct result of instrumentation
developed by Benno Schoenborn for the biological use of neutron
crystallography and scattering at Brookhaven National Laboratory. When
Benno learned of my situation in Oak Ridge, he told me to be patient
and that a suitable staff scientist position would soon be available at
Brookhaven that came with appropriate support and the freedom for
independent research. I will always remain grateful to Benno for hiring me at
Brookhaven and thereby rescuing me from scientific oblivion.

Personally, the move to Brookhaven was not easy. Vera and I liked Oak
Ridge and the beautiful countryside around it. We were not enamored of the
car-oriented commuting lifestyle of Long Island. But the job at Brookhaven
was an excellent one in a department with fine colleagues, so we moved there
in 1983. We sold our house in Oak Ridge for about 25% less than we had
paid the year before and bought a house in East Patchogue, just outside the
village of Bellport on the south shore of Long Island, about a 12-mile commute
each way from the lab. There we became lifelong friends with Karen
and Bruce Brunschwig. Bruce later played a crucial role in our ribosome effort
by synthesizing a key derivative for us, osmium hexamine.

Unlike my experience in Oak Ridge, Brookhaven gave me exactly what
they had promised. Benno said it would be nice if I did some experiments
that used neutron scattering, but that they were broadminded and I could
generally do what I wanted. They did advise me that if I wanted to get
tenure, I could not simply continue what I had been doing in Peter's lab as a
postdoc, but had to show independence. Nevertheless, my first experiment
was on ribosomes, in which I tried to settle an emerging controversy about
whether the proteins and RNA in the 30S subunit were asymmetrically
distributed. This resulted in my first independent paper being a single
author paper in Science. Since this was a decade before the internet, I wrote
a letter to my father in India when it was accepted, and about a month
later received his reply saying that he was glad I had made a good start, and
that if I continued to work hard, I might some day even have a paper in
Nature!

I also continued working on chromatin. The linker histone H1 binds
to nucleosomes and helps to organize nucleosomes into a higher order
tructure, commonly known as the 30 nm filament. I wanted to try to use
neutron scattering with deuterated histone H1 to determine its location
in the intact filament. But it was not clear how one could go about getting deuterated histones, and I spent at least a year in a futile effort to
grow Euglena gracilis in deuterated media to try to isolate histones from it.

At about this time, two crucial developments occurred. The first was that
Steve White joined me on the staff at Brookhaven. He had moved from the
Max Planck Institute for Molecular Genetics in Berlin, where in Wittmann's
department, he had been working on the crystal structures of several
ribosomal proteins. Because of our shared interest in ribosomes, he very
kindly offered to collaborate with me. Initially, I did not contribute much
to the project because I was focused on getting my own projects under way
and collaborating with Wally Mangel on the conformation of plasminogen
in solution. I began working with Steve by helping to grow large amounts of
bacteria in a Yale fermentation facility, but when I saw the low yields that were
obtained by purifying proteins from native ribosomes from Bacillus stearothermophilus,
I felt that there had to be a better way. Indeed there was, and I
could not have been in a better place to find it.

The second development was that at about this time, my colleagues Bill
Studier and John Dunn had sequenced the genome of the bacteriophage
T7, and had begun cloning a number of its genes. Importantly, because T7
RNA polymerase had its own promoter, they and their co-workers realized
that they could overexpress target genes in E. coli using the T7 promoter
and a cloned copy of T7 RNA polymerase under inducible control. They
could also use T7 RNA polymerase to transcribe target RNAs. Their work has
revolutionized biochemistry, and today there is scarcely a lab in the world
that has not at some point used their system to make large quantities of
protein in E. coli. John and Bill, as well as their associate Alan Rosenberg,
and two plant geneticists, Ben and Frances Burr, took me under their wing
and taught me all about cloning, making libraries, doing Southern blots, and
a then new technique called PCR. The result was that I was one of the few
structural biologists who was familiar with these tools at the time. Luckily, I
had two wonderful technicians, Sue Ellen Gerchman and Vito Graziano, who
were quick to learn these techniques as well, and apply them to our work.
They were later joined by the energetic Helen Kycia. These tools allowed me
to think about cloning the genes ab initio for the various ribosomal proteins
that had been crystallized from native sources. This idea worked very well
and the result was that material was no longer limiting. Moreover, in our
chromatin work, we expressed histone H1 in E. coli and used that as a route
for deuteration.

When I had been at Brookhaven for a few years, I was asked by the departmental
tenure committee what I would do if they gave me tenure. I said I
would probably stop doing neutron scattering and go away on sabbatical to
learn crystallography because that was how I could answer the really important
questions in my field. To my relief, they were quite enthusiastic about the
idea and awarded me tenure. My colleague and friend John Dunn brought a
large stick covered in aluminum foil to my home and presented the symbolic
staff to me, saying, "Welcome to the tenured staff."

Steve had constantly been encouraging me to get interested in crystallography,
saying that someone with my physics and small-angle scattering background
would have no trouble learning it. He finally kick-started me into
it by setting up, on my behalf, the first crystallization trials of the globular
domain of a linker histone, GH5. Shortly afterwards, in the fall of 1988, I
took the first Cold Spring Harbor Course in crystallography. In subsequent
years, this course was attended by several well-known scientists including Rod
Mackinnon and Art Horwich. During the following year, we obtained crystals
of GH5 that diffracted well. By then, several of the ribosomal proteins that
we had over-expressed had crystallized in previously identified conditions.
So there were several crystallographic projects that needed to be carried out.
I felt the best way to learn how to solve these structures was to go away on
sabbatical and do nothing else but work on them. There was only one place
I wanted to go for a sabbatical, the MRC Laboratory of Molecular Biology in
Cambridge, England. There were several reasons for this: it was the birthplace
of crystallography and many technical developments had occurred there; it had a huge reputation in molecular biology; the director at the
time, Aaron Klug, was considered a giant in the field of chromatin structure;
finally, Vera and I were both anglophiles and we liked the idea of spending a
year in England. I therefore wrote a letter to Aaron Klug, pointing out that
I had crystallized GH5 and would like to come for a year to learn enough
crystallography to solve its structure. He wrote back an encouraging letter,
and supported my application for a Guggenheim Fellowship, which covered
half my salary while Brookhaven paid the other half.

At Brookhaven, Bob Sweet taught me a great deal about data collection
and crystallography in general. As a result, shortly before I went to
Cambridge, Steve White and I collected data on ribosomal protein S5 using
a previously identified gold derivative, and with Bob's encouragement and
advice, Vito Graziano and I collected multiwavelength anomalous diffraction
(MAD) data on crystals of selenomethionyl GH5. With the data in hand, I set
off for Cambridge in late August, 1991, with Vera and our son Raman, who
was then 15 years old, and our daughter Tanya, who had just graduated from
Oberlin College and wanted to spend a couple of weeks touring England.

Arrival at the MRC Laboratory of Molecular Biology (LMB) was a surprise
in many ways. We had rented a large car at the airport in which to carry
all our luggage and our bicycles. Driving on the left side of the road after
an overnight flight from New York was challenging. When we got to the
Addenbrookes Hospital site, I was lost and asked someone where the famous
MRC Laboratory of Molecular Biology was, and to my great surprise, the first
few people I asked had no idea! This reminded me of the story in Crick's
autobiography "What Mad Pursuit" in which his taxi driver had no idea
where the Cavendish lab was.

I already knew that the LMB was a crowded laboratory with shakers and
refrigerators in the hallways, but coming from Brookhaven, where my department
building had originally been a bowling alley in an army base, this lack
of poshness did not bother me. When I arrived, my host John Finch, a Fellow
of the Royal Society and longstanding colleague of Aaron's, told me that
unfortunately they did not have a bench or desk for me to work at just yet. I
rather naively told him that all I needed was a small corner in his lab. John
politely smiled at this, and I found out a day later that he, a world-famous
scientist, only had a desk and a small part of a lab bench! This was still a place
where senior scientists did lab work and shared offices if they had one at all.

On my first full day there, I arrived around 9 am, and about an hour
and a half later, John came by and asked me if I would like to go up to the
canteen for coffee. I thought I had hardly done anything yet and declined,
saying I didn't drink coffee. Again, John gave me one of his enigmatic
smiles and a colleague who watched this exchange said, "He hasn't learned
our ways yet." As the days passed, I realized that these regular breaks from
work to have meals or coffee or tea allowed scientists to talk informally
together in the famous canteen on the top floor. It is also true that the human
mind can only really concentrate for a couple of hours at a time, and these
breaks re-energized people. The canteen was especially wonderful for a sabbatical visitor because I quickly got to know lots of scientists. Two of them,
Daniela Rhodes and Kiyoshi Nagai, had labs adjacent to where I worked and
were very welcoming and friendly. They have gone on to become lifelong
friends and colleagues.

There were two other important lessons I learned at the LMB. I found
that almost nobody there was working on routine problems just because they
would lead to publishable results. Rather, they were trying to ask the most
interesting questions in their field and then developing ways to address them.
The other lesson was that even very famous scientists would ask questions at
seminars that were often trivial to people in the field. It reinforced in me
the feeling that ignorance is not something to be ashamed of, and that no
question is too stupid to ask if you want to know the answer.

Although I had come with MAD data on GH5, Aaron thought that the
structure of the protein by itself might not be interesting enough and
wanted me to try to form and crystallize a complex of GH5 with DNA. The
problem was that it was not a sequence-specific protein, and it wasn't even
clear whether a duplex of DNA was an appropriate target. But being in awe
of his reputation, I started working on it, sharing a bench with his brilliant
postdoc, Wes Sundquist. After about a month, I realized that this was not
something that could be done on the time scale of my sabbatical, if ever. With
some trepidation, I told Aaron why I thought this was not a useful approach
and that I wanted to focus on solving the two structures using the data I had
brought with me. Somewhat to my surprise, he readily agreed, and I think it
increased his respect for me. When I stopped working on forming GH5-DNA
complexes, I stopped doing any bench work for the rest of my sabbatical. My
last gel was left unused on my bench, and it was with great amusement that
Wes watched it slowly dry out over the next few months.

With the help of many people, including Phil Evans, Andrew Leslie and
especially Paul McLaughlin, I learned the basic nuts and bolts of how to
solve a structure. At a crucial point early in my stay, Alwyn Jones visited from
Uppsala, and showed me how to start building a structure into maps using
his program O. The result was that by the end of my sabbatical year, both
structures were solved and eventually published in Nature. In the second of
these, GH5, I had shown that one could treat MAD data as a special case of
isomorphous replacement with anomalous scattering. This was the direct
result of a suggestion by Eleanor Dodson, who conveyed it to me through
Phil Evans. This worked extremely well, and helped to change the way that
MAD structures are solved in practice. I was particularly proud when only
a few years after having taken the first Cold Spring Harbor crystallography
course, I was invited to give a lecture in it because of my contributions to
methodology.

Move to Utah
Upon my return to Brookhaven, apart from finishing our last neutron
scattering experiment to locate H1 in the 30 nm chromatin filament, my
lab focused almost entirely on the crystallography of ribosomal proteins
and factors. However, my experience at the LMB made me unsatisfied with
the environment at Brookhaven. Although I had excellent colleagues, the
Department of Energy that ran the laboratory increasingly emphasized large
projects over individual investigator-initiated research. It became very hard
to recruit new staff scientists to the lab, particularly in new areas of biology.
The support offered to principal investigators was not sufficient to run even a
modest sized group of a few people, and grants, e.g. from the NIH, were not
easy to get, partly because of the overhead costs charged by the lab, which
were much higher than charged by many universities.

I wrote to Richard Henderson, the head of the Structural Studies Division
at the LMB to ask if they had any openings for me. He wrote back a friendly
letter saying they all liked me during my sabbatical but had no openings,
so I should just stay in touch. Not knowing Richard, I simply took this to
be a polite no. Meanwhile, my sabbatical bench mate, Wes Sundquist, was
now an assistant professor in Utah and invited me to give a seminar. A few
months later, his department asked if I would be interested in applying for
a job there. I very much liked both the faculty at Utah and the spectacular
location of Salt Lake City, nestled in a valley surrounded by beautiful
mountains. There were a lot of people interested in ribosomes and
RNA there, including Ray Gesteland, John Atkins, Brenda Bass, and Jim
McCloskey. I also particularly liked Wes and the charismatic and ambitious
crystallographer Chris Hill, who would be my immediate colleagues. When
I was offered the job, I was staggered because they offered me a salary that
was $20,000 (or 30%) more than I was making at the time, and felt they must
be expecting something of me that I couldn't possibly deliver. I accepted the
job, but a week later, I panicked at the thought of having to be totally reliant
on external funding once my start-up had run out, so I actually called up
Dana Carroll, the chairman, and said I was sorry but I couldn't come after
all. They were understandably unhappy about this sudden waffling on my
part, but fortunately kept the position open and allowed me some time to
think about it. So after some agonizing, I decided to put aside my fears about
funding and move to Utah.

The Biochemistry Department at the University of Utah was a small but
dynamic department with a relatively young and ambitious faculty working
on exciting problems. The department lived up to every promise it had
made, and within a few months, I had settled in and got my lab running.
Wes and Chris were wonderful and supportive colleagues, who occasionally
acted as my psychiatrists whenever I would panic about failing. My chairman,
Dana, became a close personal friend because we were similar in age and had
common interests such as chamber music and hiking.

Bob Dutnall, who had done his Ph.D. at the LMB under Daniela Rhodes,
joined me as a postdoc to work on chromatin modifying enzymes. We
went on to solve the first structure of a histone acetyltransferase, Hat1, in
collaboration with Rolf Sternglanz from Stony Brook. We were helped by a
technician, Adrian Hahn. Except for Bob, and another postdoc, Mabel Ng,
the lab was now focused on solving ribosomal protein structures. Bil Clemons
joined the lab initially to work on ribosomal protein S15. Brian Wimberly
had turned down a faculty position to do a second postdoc with me. He
first solved a ribosomal protein structure, and then solved the structure of
the first protein-RNA complex in the ribosome, that of L11 with a piece
of RNA that binds to it. This part of the ribosome is also the target of
antibiotics such as thiostrepton. The effort involved in this made
me realize how much work it would take to solve all of the binary
protein-RNA complexes in the ribosome, and how little we would learn
about how the ribosome actually works from that effort. Even before
coming to Utah, I had ideas of solving the structure of the ribosome,
beginning with its small or 30S subunit. These ideas and their
scientific consequences are outlined in my Nobel lecture and will not be
discussed here. But how it happened from a human point of view is perhaps
interesting.

My first task was to convince someone in the lab that this was a worthwhile
project. Brian was cautious. Perhaps he knew too much about the difficulties,
and also because it was his second postdoc, felt he couldn't take such a risk.
So he decided to focus on solving the complex of protein S7 with its binding
site on RNA. I made a friendly but wildly optimistic bet with him that we'd
solve the entire 30S (including S7 of course) before he solved his complex. Another postdoc, Matt Firpo, worked on the problem for about a year, but
had to leave when his funding ran out.

The project really took off when the two graduate students came on
board. Bil Clemons was a smart and very ambitious student who fortunately
was at a stage where he was willing to gamble on something potentially big.
His eyes lit up at my suggestion and he immediately said he would take on
the project. He worked on two small proteins to learn crystallography first
before devoting his full attention to the 30S subunit. John McCutcheon
also enthusiastically decided to devote full time to it. I knew I needed
Brian Wimberly on board because of his encyclopedic knowledge of RNA
structure and the literature on ribosomes, and as soon as we had made tangible
progress, he too joined the team. With a capable technician to assist us,
Joanna May, we were off and running.

As soon as we started, my insecurities about funding again set in. I could
just imagine writing a grant application to NIH saying that we had no good
crystals of the 30S subunit but had some ideas about how to get them, and
that although a group had been working on good crystals of the 50S subunit
for almost a decade, we had some ideas for how to solve our structure if
we got good crystals. Having served on study sections myself, I could just
imagine the peals of laughter that would go around the table as my application
was considered. On the other hand, I knew that the LMB, where I
had done my sabbatical, had a longstanding tradition of supporting exactly
this kind of difficult but fundamentally important project. Apartment from
funding issues, I felt I would have access to world leaders in crystallographic
methodology who could help me if I ran into technical problems.

So I wrote again to Richard Henderson, who by that time had also become
the director of the LMB, and we agreed that I would visit on my way to a
ribosome meeting in Sweden. After my talk on ribosomal proteins, Richard
and Tony Crowther (who was joint head of the division with Richard) chatted
with me for a couple of hours on the "ribosome problem." They were interested
in my ideas, what the competition was likely to be, what approaches
had failed, what resolution one would have to reach to achieve a significant
breakthrough in understanding and how long that was likely to take. The
conversation was unlike any other job interview. There was no discussion
of space, salary or equipment, just about science and ideas. At the time,
I had no crystals; nevertheless Richard wrote shortly after my visit saying
they were interested in supporting me, and would let me know when they
would have the additional space to accommodate me. Aaron, Daniela and
Kiyoshi also expressed support for the idea of my move there. A few months
later, Richard wrote again to say that indeed the space had materialized. I
suddenly had to make what was one of the hardest decisions of my life:
whether to gamble everything on going to the LMB and work exclusively on this
project, which would involve taking a large salary cut and leaving our families
(including our grown children) in the U.S.A., or to continue working in
Utah, where I would probably have to hedge my bets by working on safer
projects simultaneously. In the end, I decided that the structure of the ribosome was the most important goal in my field, the time was ripe for an
attack on it, and it would be a mistake to be distracted from it by other
projects because there was only a narrow window of opportunity before
other groups entered the field that had so long been dominated by just one
person, Ada Yonath.

Most people thought that it would be insane to move to England, staking
all on this one risky project. Two people who encouraged me to go were
Peter Moore and Steve Harrison. Both recognized from their own careers the
ambition to solve a fundamental problem regardless of the challenges. While
many in my family were ambivalent, my mother encouraged me to put aside
my fears and go to Cambridge and give it a shot. Vera and I finally decided
to leave Utah, where we were very happy, take a 40% salary cut and move to
the LMB. It was a very difficult moment for me when I had to tell Dana, Wes
and Chris of my decision. I had to stay there for another year to work out the
logistics of moving. During this time, I came to realize how truly wonderful
my Utah colleagues were. They put aside any disappointment at my leaving
and were both understanding of my decision and supportive of my efforts
during my last year, helping in every possible way in our work. In one last
hiccup, I almost didn't move to the LMB when I found I was going to lose
John McCutcheon because he had personal reasons not to move, while
during the student recruitment day in Cambridge I found myself unable to
attract anyone to this effort. Fortunately, two people courageously agreed
to join my lab at the LMB without ever having met me: Andrew Carter, who
joined me from Oxford as a Ph.D. student, and Ditlev Brodersen, a postdoc
who came highly recommended to me from Århus in Denmark, where I
knew his supervisor Morten Kjeldgaard. Their joining me was a stroke of luck
and meant we would have a viable team at the LMB.

With the decision to move to the LMB made, I decided to focus entirely on
the 30S subunit. Within a few months we had crystals, and a few months later,
we had cracked the problem of getting them to diffract well. This was largely
due to John and Bil's willingness to try completely new approaches to purifying
the 30S subunit and to their sheer dedication and hard work. We were
also helped by Malcolm Capel's willingness to let us screen lots of our initial
crystals at the NSLS at Brookhaven. Shortly before our move to the LMB, we
collected data on several derivatives to 5–6 Å resolution.

Work at the MRC Laboratory of Molecular Biology
I moved to Cambridge in April of 1999, while Brian, Bil and Joanna
stayed behind. The result was that I was able to make use of the LMB's
computing resources to try several phasing runs in parallel, and send the maps
to Utah where Brian and Bil would look at them. Because of the 7 hour time
difference, we may have been the only group that actually speeded up to
some extent as a result of a move. I suggested to Brian, who up to that point
was focusing entirely on the RNA in the maps, that some of the tubes we
were seeing were probably alpha helices of proteins. By the time I left that day, he told me he had identified a protein, S6, in the maps. The next morning,
I was amazed when I came to the LMB to find out that he had identified
all of the proteins of known structure in the maps! He said it was like
eating potato chips: once he had identified one, he couldn't stop. With his
knowledge of the protein-RNA interaction data, and his feeling for RNA folds,
he went on to trace the entire central domain of the 30S subunit, and also
identify a protein of previously unknown structure, S20. So only a few months
after my move to Cambridge, with the rest of my lab still in Utah, we had
made a major breakthrough. When I revealed our findings at the triennial
ribosome meeting in Denmark in June, I could sense the shock in the
audience, especially since virtually none of them knew we were working on
the problem. Soon afterwards, our work was published in Nature in August,
1999 with much fanfare.

Although Tony, Kiyoshi and Daniela were very welcoming to us, we had
trouble settling into Cambridge. Vera and I were shocked by the rapidly increasing
housing prices, and for a while despaired of ever finding a house we
could actually buy since we kept being outbid on the many offers we made.
When I was away on a synchrotron trip at Brookhaven, Vera found a house in
Grantchester, a historic village just outside Cambridge that was within bicycling
distance of both the city center and the LMB, and made a bid that was
actually accepted. So we finally had a permanent home in Cambridge. By this
time, Brian and Bil had moved from Utah, and we needed to focus on getting
to high resolution.

Solving the 30S Subunit Structure
Getting to the high-resolution structure of the 30S subunit was beset with
problems, which are described in the Nobel lecture. This was a particularly
stressful time for me and my lab members. The Yale group of Tom Steitz,
Peter Moore and their colleagues was making steady progress with their
structure of the 50S subunit. More significantly for us, soon after we had
decided to focus on the 30S subunit in Utah, I had found out that Ada
Yonath, who had first crystallized the 50S subunit and had been working on
determining its structure for over a decade, had now essentially switched to
determining the 30S subunit structure using crystals obtained by a slightly
different route. So instead of having a quiet niche to myself, we were in a
flat-out race. Our progress slowed down because the limitations of the
crystals meant that we could not collect data to high resolution at
Brookhaven. The one high intensity beam line where we could orient crystals
about a mirror plane was at the new SBC 19ID beam line at the Advanced
Photon Source (APS) in Argonne. We felt this orientation was necessary
to eke out the best anomalous signal from our crystals. But the beam line
was not yet open to the public, since it was just being commissioned. Our
competitors had already collected data there but it was not clear that we
would be able to get time on it. Fortunately, as a result of a request from
Peter Moore on our behalf to Paul Sigler, who was on the advisory board
for that beam line, we were awarded beam time 2–3 months hence, in late
February. It was tragic that only days after he interceded on our behalf, Paul
suddenly died of a heart attack.

Given the competition, we wanted to ensure that our data collection at the
APS was a success, since it was not clear that we could avoid being scooped
if that trip failed. Bil Clemons and Rob Morgan-Warren, a technician who
joined us at the LMB, froze over a thousand crystals in the cold room while
listening to Johnny Cash on a mini stereo system. We then would take the
crystals to Daresbury to screen and group them into crystals that had similar
cell dimensions and diffracted well. Not content with this, I sent Bil on a solo
trip to Brookhaven where he collected low-resolution data on each of the
derivatives to make sure they were bound. He was completely exhausted after
having spent 48 hours without sleep.

During our crucial trip to the APS in late February 2000, four of us worked
in 12 hour shifts using a large spreadsheet that told us which crystals we
had to look at next. Ditlev used his computing skills to streamline our data
collection and analysis procedures. We calculated an anomalous difference Fourier map while still at the beam line, and when I saw the large number
of strong peaks for our best derivative, much to Rob's amusement, I started
dancing around the office saying, "We're going to be famous!"

The maps from the improved data were stunning, and we were on our way
to building the structure. With five of us working long hours, were able to
build a complete atomic model for the subunit within weeks. Even before we
had finished, Andrew Carter had crystallized the subunit with three different
antibiotics, and seeing them directly in difference Fourier maps was another
great highlight.

The structure of the 30S subunit led to a number of follow-up studies
on antibiotics and ligand binding. The most important of these, largely
carried out by James Ogle, led to understanding how the ribosome ensures the
accuracy of translation during decoding of the genetic message. Our studies
on decoding continue to this day in the context of the whole ribosome.

The Whole Ribosome and Its States
It was always clear that we would need high-resolution structures of the
entire ribosome in many states to understand the underlying mechanisms
of translation. This problem turned out to be much harder than we had
anticipated, given the speed with which our 30S work had been
accomplished. A stream of dedicated postdocs and students wrestled with
the problem for many years. Frank Murphy, assisted by Mike Tarry, worked
out procedures for how to make ribosomes that were pure enough to
crystallize. Tina Daviter and Ann Kelley introduced methods to purify large
quantities of ribosomes. Maria Selmer and Christine Dunham collaborated
on a project that led to high-resolution crystals of the whole ribosome with
mRNA and tRNA bound, and they were joined by Frank, Sabine Petry and
Albert Weixlbaumer to build the structure. This was another frantic effort
that had echoes of the 30S race, because we had suddenly heard that Harry
Noller, whose lab had solved the whole ribosome at low resolution, now had
improved crystals of a ribosome complex and we did not want to be beaten to
it after having spent so many years on the problem.

Of the current members of the lab, Martin Schmeing, Caj Neubauer,
Rebecca Voorhees, Hong Jin and Yong-Gui Gao work on many different
aspects of the translational pathway including elongation, termination and
quality control. Two postdocs, Leong Ng and Israel Sanchez have boldly
decided to tackle the eukaryotic ribosome, and Alexey Amunts is involved
in a joint collaboration with John Walker on the mitochondrial ribosome.
Throughout all this, Ann Kelley has become the senior member of the lab.
As a longstanding research associate, she is the person who holds the lab
together, training new people, making essential reagents, and becoming
the general repository of knowledge for the lab. She does this in her usual
matter-of-fact way without complaining, and given my other duties in the last
few years, the lab would run into great difficulties without her.

Life in Cambridge
Despite our having enjoyed Cambridge thoroughly during my sabbatical
year, Vera and I were surprised to find our permanent move there in 1999
difficult. The pay cut and the increase in cost of living were less of a problem
because we simplified our lives and never really noticed a difference in our
standard of living. But we had left our families, especially our children,
behind and there were just the two of us in England.

That isolation has been compensated for by life in Cambridge. Our simple
car-free life style, coupled with the rich cultural life of Cambridge and the
proximity of London has made our daily lives in Cambridge a pleasure.
We have made many good friends who have enriched our lives. At the lab,
Kiyoshi Nagai, Daniela Rhodes, Phil Evans, and Andrew Leslie are among
many people with whom I have become friends over the years. Every Easter,
Vera and I join Phil and his wife Carol, along with Guy and Eleanor Dodson,
and Peter and Judith Murray-Rust, to go on a walking holiday. These trips
have allowed me to see some of the beautiful countryside of England. We
also take bike rides and walks with Alan Coulson (who was Fred Sanger's long
time associate and a coauthor on the dideoxy sequencing paper) and his wife
Sue, and Ray and Judy Steward. So over the years, we have come to regard
England as home.

Fortunately, our family has also survived the transatlantic separation. Tanya
is a physician with a master's in public health who works mainly with poor
immigrants in Portland, Oregon. Raman, after graduating with a physics
degree, obtained a master's degree in music from the Juilliard School and
is a cellist with the Daedalus Quartet. My sister Lalita is on the faculty at the
University of Washington in Seattle where her work on TB using novel model
organisms for both the bacterium and host is allowing her to make important
discoveries. My parents lived near her in Seattle, but sadly, my mother, who
first encouraged me to go into basic science and later to go to Cambridge,
died two years before the Nobel Prize for the ribosome was awarded. My
father, who is 84 years old, helped to raise my sister's children and remains
physically active and mentally alert, cleaning two houses, cooking and
doing the laundry, in addition to trying to establish educational programs in
India. Our geographical isolation from our family has been mitigated by the
increasing ease of communications, including the use of programs such as
Skype.

Reconnecting with India
Since I left India at the age of 19, I had been back only three times in about
28 years. One by-product of my travels was that in early 2002, I was asked to
give the first G.N. Ramachandran Memorial Lecture in Chennai. On this
trip, I also visited the Indian Institute of Science in Bangalore for a day.
This was my first visit to India in 13 years, and my first ever interaction with
the Indian scientific community. It started a process by which I not only
became more familiar with scientific research at a few institutions in India, but also got to know individual scientists well. In the last few years, I have
had a G.N. Ramachandran visiting professorship at the Indian Institute of
Science in Bangalore, and have used it to escape the dark and dreary late
December – early January period in Cambridge and work in Bangalore on
papers and reviews, give lectures and talk to colleagues and especially young
scientists there. This reconnection with my Indian roots has given me great
satisfaction, and I was touched when in 2008 the Indian National Science
Academy elected me as a foreign fellow.

The Politics of Scientific Recognition
People go into science out of curiosity, not to win an award. But scientists
are human and have ambitions. Even the best scientists are often insecure
and feel the need for recognition. Our ribosome work led to lots of invitations
to give seminars and speak at conferences. It resulted in my election
to the Royal Society and the U.S. National Academy of Sciences and also led
me to receive a prestigious European prize, the 2007 Louis-Jeantet prize for
medicine. Thus in both my scientific efforts and the recognition for it, I had
succeeded beyond my wildest dreams.

Although few scientists are foolish enough to enter a field to win a Nobel
Prize, ever since the 30S subunit had been solved, people would regularly
bring up "the Prize" in conversations whenever I went to conferences or
give seminars. It was clear to me that the ribosome was at least as important
as other structures that had been awarded the Nobel Prize. But there were
many more than three people who had contributed to the ribosome, even if
one only counted principal investigators, which itself is a fictional view of the
way modern science is done.

While we were solving the structure of the 30S subunit, I had mostly
refused to be distracted by going to meetings to speak about our work. So
it was something of a shock when only a couple of months after the atomic
structures of the subunits came out, a prize in the U.S.A. was awarded to
just one aspect of the ribosome, peptidyl transferase. It seemed to me that
instead of waiting for the impact of the ribosome work to become clear and
then thinking hard about what had really made a difference to the field,
the committee had hurriedly decided on which three people they wanted
to honor and then written a citation around them that would exclude the
others. Richard Henderson, my director, suggested that I should accept more
invitations to meetings and talks to get our story known if only to get proper
recognition for our work, regardless of prizes.

Deep down, I felt that the scientific event that transformed the field more
than anything else was the determination of the atomic structures of the
ribosomal subunits and the functional studies that followed as a result, to
which we had made a major contribution. However, international prizes
for work on ribosomes always seemed to go to other people. So over the
years, I had gradually come to accept that I would probably not get a major
international prize for the ribosome, least of all the Nobel Prize. Once I had accepted that, I felt liberated and happier, but I have to confess that I felt
some trepidation each October. Every time I learned the Nobel Prize was
for something other than the ribosome, I would be relieved because it was a
postponement of what I felt would be the inevitable disappointment. As the
years went by, it seemed to me and many other scientists that there would
never be a Nobel Prize for the ribosome because the problem of choosing
three people out of all the contributors appeared insurmountable.

The Nobel Prize and Its Immediate Aftermath
On October 5, 2009, the Nobel Prize for Physiology and Medicine went for
work on telomerase. Since the Chemistry prize had been awarded for biological
work the previous year, I was confident that it would not be awarded
for the ribosome that year. On the morning of October 7, I was halfway to
work when my bicycle developed a flat tire. As a result, I came in quite late
and somewhat irritated, and had completely forgotten that it was the day the
Chemistry Prize was going to be announced. So when the phone rang soon
afterwards and a voice said it was an important call from the Royal Swedish
Academy of Sciences, I immediately suspected it was a prank orchestrated
by one of my friends like Rick Wobbe or Chris Hill, who like practical jokes.
When Gunnar Öquist came on the line and started talking to me, at first I
simply refused to believe him and even complimented him on his Swedish
accent. Finally, after he was done, I asked if I could speak to one of the committee
members, Måns Ehrenberg, whom I knew personally. When I heard
his voice, it was with a shock that I realized it was true, a feeling that was
reinforced when Anders Liljas and Gunnar von Heijne also came on the line
to congratulate me. Two members of my lab, Martin Schmeing and Rebecca
Voorhees, had desks just outside the open door to my office and had overheard
my end of the entire conversation. They did not share my skepticism
and could hardly contain themselves. By the time I got off the phone, they
were jumping up and down, and Martin popped open a bottle of champagne
he had been saving to celebrate the publication of a paper that had just been
accepted in Science. In the intervening minutes between the phone call and
the public announcement, I was unable to get hold of Vera, because she was
taking a walk with Tanya and does not use a mobile phone. It was 2 am in
Seattle and 5 am in New York, so I did not want to wake up my father, sister
or Raman. Unfortunately, the press was not so considerate.

It was not until I saw the public announcement on the Nobel web site that it
fully sank in. Within a few minutes, the phone rang and did not stop ringing
for two days. My colleagues at the LMB, many of whom had supported me when
I had nothing but an idea, were delighted. They organized the customary
drinks celebration in the canteen, for which Mike Fuller bought and served the
champagne as he had for all the previous Nobel Prizes awarded to scientists
here. After the celebration, Vera and I walked my bicycle home in the rain.
It was touching to get congratulatory messages from old friends and
scientific colleagues around the world. I was especially moved by messages
from colleagues in the ribosome community including my mentor Peter
Moore and Joachim Frank, both great scientists who had made major contributions
to the field and were justifiably contenders for the prize themselves.
Peter was particularly (and typically) gracious, and seemed proud that his
protégé had done so well. Much was made of my prize in India, and I found
myself the subject of an entire nation's celebration. I was taken aback by the
flood of emails from complete strangers in India, and when they continued
unabated for several days, I overreacted to what I felt was an intrusion on
my ability to carry out my work. This angered many people there and a
clarification I made only partly mollified them.

The Nobel week in Stockholm in December was surreal and memorable.
After Sweden, I went on my usual annual visit to India, but this time with
some trepidation because I did not know what the reaction to me would be
given the email controversy. I need not have worried, because I was overwhelmed
by the warmth and affection from both members of the public and
my scientific colleagues there. I was honored that the Government of India
decided to bestow upon me their second highest civilian award, the Padma
Vibhushan. I have come to realize that I have inadvertently become a source
of inspiration and hope for people in India simply by the fact that I grew up
there and went to my local university, but could nevertheless go on to do well
internationally.
On my return to Cambridge in early January, things slowly began returning
to normal after the euphoria of the autumn. I began to realize that the
Nobel Prize could be seen not just as an affirmation of my past work but also
as an encouragement to continue to work on interesting problems. Certainly,
it seems to have fired up people in my laboratory, and I look forward to the
struggles ahead as we try to answer some of the hard questions in our field
and beyond. Looking back on my life so far, I feel a deep sense of gratitude
for having been able to lead such a rich life, both intellectually and personally.

This autobiography/biography was written
at the time of the award and later published in the book series Les
Prix Nobel/Nobel Lectures/The Nobel Prizes. The information is sometimes updated with an addendum submitted
by the Laureate.